RIG-I-Inducing Small Molecules Potently Inhibit HMA-Resistant AML Through Igniting the Overloaded dsRNA Arsenal

  • Adv Sci (Weinh). 2025 Jun 26:e14477. doi: 10.1002/advs.202414477.
Xueqin Chen  1 ,  Jiaqi Wu  1 ,  Yuntong Li  1 ,  Jiayu Huang  1 ,  Xiangqin Weng  1 ,  Jiale Wu  1 ,  Shujun Xiao  1  2 ,  Huaxin Song  1 ,  Zhengyuan Wang  1 ,  Ni Yan  1 ,  Fangfang Shi  1 ,  Derun Zheng  1  2 ,  Kai Tan  1  2 ,  Hesong Zhang  1 ,  Jingyi Cui  1  2 ,  Wen Wu  1 ,  Wei Wu  3 ,  Sujiang Zhang  1 ,  Min Lu  1
Affiliations
  • 1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3. Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
PMID: 40568903 DOI: 10.1002/advs.202414477
Abstract

DNA hypomethylating agents (HMAs) are widely used to treat acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), but most treated patients relapse and lack standard treatment options. Using high-throughput screening, the approved all-trans retinoic acid (ATRA) is identified that exhibit high selectivity in killing HMA-resistant AML cells compared to parental cells. Mechanistically, HMA-resistant cells are overloaded with DNA hypomethylation-associated endogenous viral double-stranded RNA (dsRNA) which, however, fails to trigger an Anticancer interferon (IFN) immune response due to downregulation of dsRNA sensor retinoic acid-inducible gene I (RIG-I). ATRA compensates for RIG-I expression, thereby re-triggering IFN response and potently inhibiting HMA-resistant AML cell lines, xenograft mice, and patient-derived primary cells. A library of potential RIG-I-inducing compounds is rationally constructed and screened, in which the approved M3 AML treatment drug tamibarotene (TAM) exhibits strikingly 28036-fold selectivity and 779 pm IC50 in killing HMA-resistant AML cells. ATRA and TAM do not selectively inhibit p53-mutant Cancer cells. Together, this study uncovers a common resistance mechanism in HMA-treated AML patients and, in addition, provides highly potent and selective agents that can overcome resistance through re-triggering IFN Anticancer immune response.

Keywords
RIG‐I; acute myeloid leukemia; anticancer immune response; hypomethylating agent; interferon.
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